1. A Review of Isoniazid Preventive Therapy (IPT): benefits and challenges

2. Tuberculosis Global Epidemiology
In 2016:
10.4 million cases
1.7 million deaths
deaths among HIV+,
Ninth leading cause of death worldwide
Leading cause from a single infectious agent, ranking above HIV/AIDS

3. Your Country, WHO TB 2017 Case notifications: XXX
TB Incidence: XXX per 100,000
HIV+ TB patients: XXX (XXX)
HIV+ screened for TB: XXX
HIV+ given INH: XXX
XXX deaths in TB/HIV pts

4. Latent Tuberculosis Infection (LTBI)
M. tb contained by the immune system
Results in a dormant or latent stage of TB
From this latent stage, the bacteria can reactivate to cause TB disease at any time
Treatment of latent TB infection (LTBI) can decrease the risk of reactivation

5. Isoniazid Preventive Therapy (IPT)
INH is the mainstay for latent TB treatment
Effectiveness is 60-90%
Due to variable adherence, actual effectiveness is 25-90%
Trial comparing IPT for 12, 24, 52 weeks
24 weeks decreased TB by 65%
Less hepatitis than with 52 weeks
Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bulletin of the World Health Organization 1982;60:

6. IPT preventing TB in HIV+ Children
Frigati et al. 2011, South Africa
Double blind, placebo controlled trial in HIV+ children on ART
DSMB terminated placebo arm at 4 months due to demonstrated benefit of INH on mortality
Children receiving placebo were switched to INH
Concluded: IPT reduces the risk of TB in HIV+ children on ART by 0.23 ( 95% CI )
Frigati LJ, Kranzer K, Cotton MF, Schaaf HS, Lombard CJ, Zar HJ. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax 2011;66:

7. IPT preventing TB in HIV+ Children
Further evidence…
Grey et al. 2014, South Africa
RCT to assess the efficacy, tolerability and safety of IPT in HIV+ children on ART
85 received INH, 82 received placebo
4 cases of TB in INH group, 7 in placebo group, all susceptible to INH
Conclude: IPT is safe and well tolerated in HIV+ children on ART
Gray DM, Workman LJ, Lombard CJ, Jennings T, Innes S, Grobbelaar CJ, Cotton MF, Zar HJ. Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study. Int J Tuberc Lung Dis Mar;18(3):322-7.

8. IPT in HIV+ Children on ART
Ayieko et al. Meta-analysis, 2014
Included 8 RCTs of IPT in children
confirmed that INH is more efficacious in preventing TB
Concluded: IPT reduces the risk of developing TB by 59% among children aged 15 years and younger excluding infants (95% CI )
Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC infectious diseases 2014;14:91

9. Optimal duration of IPT?
All completed a baseline survey, but control group otherwise untouched.
78,744 miners enrolled, randomized into 15 clusters
Intervention group: TB screening & IPT x 9 mos
Primary outcome: TB incidence during 12 mos after intervention ended

10. IPT in high risk populations
Among 63,174 miners with outcomes:
887 TB cases in the intervention clusters
856 in the control clusters
TB incidence: 3.02 & 2.95 cases/100 person-years
Conclude: Mass screening & treatment for LTBI had no significant effect on TB in South African gold miners
BUT… IPT was successful in preventing TB during treatment
Mistake to conclude IPT not beneficial, suggests longer duration indicated while remain at high risk

11. G Churchyard: “IPT as an Umbrella”

12. Current IPT Delivery is Inadequate
Among eligible
Children: only 8% to 20% receive IPT
HIV+ patients: Far below global target of 50%

13. Why current IPT delivery is inadequate ?
Focus historically on TB disease treatment not prevention
Difficulty excluding TB disease
Long duration of IPT
Overestimation of the complications of INH
Concerns about toxicity and generation of INH resistant TB are unsubstantiated
Inability to ensure IPT adherence: - LTBI is asymptomatic, therefore testing is provider-initiated
Because patients are asymptomatic, less motivated to take long treatment

14. Additional References
Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC infectious diseases 2014;14:91.
Global tuberculosis report Geneva: World Health Organization; 2017
UpToDate 2014 : Tuberculosis in children, LV Adams & JR Starke
UpToDate 2014: Treatment of Latent TB in HIV negative patient, CR Horsburg
Targeted tuberculin testing and treatment of latent tuberculosis infection. American journal of respiratory and critical care medicine 2000;161:S221-4
Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. The New England journal of medicine 2002;347:
Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bulletin of the World Health Organization 1982;60:555-64